CN111793021B - Method for preparing 6-cyano-pyridine-2-ketone derivative through safe cyanidation - Google Patents
Method for preparing 6-cyano-pyridine-2-ketone derivative through safe cyanidation Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a 6-cyano-pyridine-2-ketone derivative by heating and reacting ammonium salt and N, N-dialkyl formamide serving as a cyanogen source under the condition promoted by copper salt. The reaction has the advantages of simple and easily obtained reaction raw materials and catalysts, low price, utilization of oxygen under normal pressure, mild reaction conditions, safety, high efficiency, wide reaction substrate universality, high yield of target products, simple reaction operation and post-treatment process and the like. The process of the present invention further simplifies the synthesis of 6-cyano-pyridin-2-one derivatives and the product types are further extended.
Description
Technical Field
The invention belongs to the technical field of safe cyanidation, and particularly relates to a 2-pyridone derivative C 6 A selective cyanidation reaction, in particular to a method for preparing 6-cyano-pyridine-2-ketone derivatives by taking ammonium salt and N, N-dialkyl formamide as safe cyanogen sources.
Background
Pyridine-2-ketone and its derivatives are an important class of building blocks, widely found in natural compounds, bioactive molecules and prodrugs (see (a) med. res. rev.1999,19,497.(b) chem. Biodiversity 2005,2,1.(c) adhesives chemicother.2003, 47,1805.(d) j. am. chem. soc.1966,88,3888.(e) n.engl.j.med.2014,371,2353.(f) j.nat. prod.2009,72,2098.(g) j.anitibis. 1981, 56. (h) nat. prod.2010, 27, 1168.(i) Future. chem.1332012, 4,2311.(j) adhesives. 1988., 2016, 5932. 2016). Therefore, organic synthetic chemists have conducted extensive research on the functionalization of pyridin-2-ones. Whereas for the functionalization of 2-pyridone derivatives, direct functionalization of the 2-pyridone mother ring is undoubtedly preferred, wherein the prior art also widely reports extensive studies on direct functionalization of the C3, C4, C5 and C6C-H bonds of the 2-pyridone ring (see (a) chem. -eur.j.2013,19,7691. (b) j.org.chem.2014,79,1377.(C) chem.commu.2014, 50,6879.(d) j.org. chem.2015,80,296.(e) org.lett.2019,21,8110.(f) Synthesis 2017,49,4745.(g) chem.sci 2012, 3. (H) chem.comm. 51,17744. (H) chem.27, 42 j.42 j., 42 j.2015., 2016, 84, 2016, 84 g.2016, 2016, 14 g) chem.2016, 26, 2016, 84, 14, 26, 14, 26, 14, 26, 8, 14,7, 8, 14, 8, g.
Aromatic nitrile compounds are also widely present among active pharmaceutical molecules, natural compounds, pesticides, dye molecules (see (a) j.med.chem.1995,38,1106.(b) bioorg.med.chem.1996,4, 1379.(c) Drugs 2005,65,2379.(e) adv.synth.catal.2009,351,3027.(f) chem. soc.rev.2011,40,5049.(g) chem. -eur.j.2011,17, 4217-. Cyano groups are also conversion precursors for other important Functional groups (see (a) chem. Rev.1988,88,765.(b) org. Lett. 2009,11,3582.(c) Med. chem. Lett.2005,15,29.(d) Larock, R.C. Comprehensive Organic Transformations: A guide to Functional Group precursors; VCH: New York, 1989.). In the past, Sandmeyer reactions and Rosenmund-von Braun reactions using diazonium salts or haloarenes have been widely used in the synthesis of aromatic nitriles (see (a) be. dtsch. chem. ges.1884,17,1633.(b) chem. rev.1947,40,251. (c) be. dtsch. chem. ges.1919,2,1749), but such methods require the use of equivalent amounts of cuprous cyanide, a toxic reagent, and higher reaction temperatures. In the past decade, many efforts have been made to cyanide C — H bonds directly by transition metals, but highly toxic cyanide sources such as sodium cyanide and potassium cyanide (see j.am. chem. soc.,2011,133,10999.) have also been used, as well as expensive metal catalysts. For the efficient synthesis of 2-cyano-6-hydroxypyridine, the conversion is still carried out using 6-halopyridone as starting material (see: org. Lett.2017,19,5760), requiring a complex source of cyanogen and harsh reaction conditions. Therefore, the green, efficient and cheap synthesis method of the 6-cyano-pyridine-2-ketone is further developed, and the method not only has higher scientific research value, but also has wide application prospect.
Disclosure of Invention
The invention aims to develop a method for preparing 6-cyano-pyridine-2-ketone derivatives by taking ammonium salt and N, N-dialkyl formamide as safe cyanogen sources, wherein the method takes the ammonium salt and the N, N-dialkyl formamide as the cyanogen sources, and promotes the reaction of the 2-pyridine-2-ketone derivatives, the ammonium salt and the N, N-dialkyl formamide by transition metal to prepare the 6-cyano-pyridine-2-ketone derivatives. The method has the characteristics of simple and easily obtained required raw materials, mild reaction conditions, safety, high efficiency, simple and convenient post-reaction treatment, high reaction yield and the like.
In order to achieve the purpose, the invention is realized by the following technical scheme:
a process for the preparation of 6-cyano-pyridin-2-one derivatives from ammonium salts and N, N-dialkylformamide as a safe source of cyanogen by the following steps:
(1) adding copper salt, 2-pyridone derivative shown in formula 1, ammonium salt shown in formula 2 and N, N-dialkyl formamide shown in formula 3 into a reactor, and then heating and stirring the reactor at the temperature of 100 ℃ and 150 ℃ in an oxygen atmosphere for reacting for 8-36 h;
(2) the reaction is terminated, cooled to room temperature, and post-treated to obtain the 6-cyano-pyridin-2-one derivative represented by formula 4.
The reaction formula is as follows:
in the above reaction formula, R represents 1,2 or 3 substituents on the 2-pyridone ring to which it is attached, each R substituent being independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy, -CN, -NO 2 、-OH、C 1-6 Acyl radical, C 1-6 And (4) acyloxy.
R 'represents 1,2, 3,4 or 5 substituents on the attached pyridine ring, each R' substituent being independently from each other selected from hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy, -CN, -NO 2 、-OH、 C 1-6 Acyl radical, C 1-6 An acyloxy group; or two adjacent R 'substituents are linked to each other and together with the carbon atom linking the two R' groups to form a five-to seven-membered ring, with or without heteroatoms.
X represents an anion of an ammonium salt.
R 1 ,R 2 Independently of one another, from C 1-20 An alkyl group.
Preferably, in the above reaction scheme, R represents 1,2 or 3 substituents on the 2-pyridone ring to which it is attached, each R substituent being independently selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, acetyl, -CN, -NO 2 。
R 'represents 1,2, 3,4 or 5 substituents on the attached pyridine ring, each R' substituent being independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, acetyl, -CN, -NO 2 (ii) a Or two adjacent R 'substituents are linked to each other and together with the carbon atom linking the two R' groups form a five to seven membered ring free of heteroatoms.
X represents an anion of an ammonium salt selected from F - 、Cl - 、Br - 、I - 、OAc - 、HCO 3 - 、CO 3 2- 、NO 3 - 、 SO 4 2- 。
R 1 ,R 2 Independently of one another, from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.
Most preferably, in the above reaction scheme, R represents 1,2 or 3 substituents on the 2-pyridone ring attached, each R substituent being independently selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy.
R 'represents 1,2, 3,4 or 5 substituents on the attached pyridine ring, each R' substituent being independently from each other selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy; or two adjacent R 'substituents are linked to each other and together with the carbon atom linking the two R' groups to form a benzene ring structure.
X represents an anion of an ammonium salt selected from I - 。
R 1 ,R 2 Independently of one another, from methyl or ethyl.
According to the method of the present invention, in step (1), the copper salt removes copper sulfate (specifically, CuSO) 4 ·5H 2 O) in addition to other copper salts, e.g. Cu (OAc) 2 、CuCl 2 、CuBr 2 、Cu(OTf) 2 、Cu(NO 3 ) 2 Moderate to excellent yields can be achieved with respect to CuOTf, CuCl, CuBr, CuI. Preferably, the copper salt is Cu (OAc) 2 。
According to the aforementioned method of the present invention, in the step (1), the pressure of the oxygen atmosphere is 1atm (0.1 MPa).
According to the aforementioned method of the present invention, in the step (1), the reaction temperature of the heating and stirring reaction is 100 ℃ and 150 ℃, and the reaction time is 8-36 h; preferably, the reaction temperature of the heating stirring reaction is 130 ℃, and the reaction time is 20 h.
According to the aforementioned method of the present invention, in the step (1), the feeding molar ratio of the 2-pyridone derivative represented by the formula 1, the copper salt and the ammonium salt represented by the formula 2 is: 1 (0.5-2) and 1-3); preferably, the feeding molar ratio of the 2-pyridone derivative shown in formula 1, the copper salt and the ammonium salt shown in formula 2 is: 1:1:1.5. The N, N-dialkyl formamide shown in the formula 3 is used as a reaction solvent in the reaction of the invention, and the dosage of the N, N-dialkyl formamide can be determined conventionally so as to ensure that the materials are fully dispersed and mixed and are stirred smoothly for reaction.
According to the method of the invention, in step (2), the post-treatment operation is as follows: quenching the reaction liquid by using a saturated sodium thiosulfate solution, extracting by using ethyl acetate, combining organic phases, removing the solvent by decompression and concentration, and then carrying out column chromatography separation and purification on the residue (the elution solvent is a mixed solvent with a volume ratio of dichloromethane/methanol of 200: 1-20: 1) to obtain the 6-cyano-pyridine-2-ketone derivative shown in the formula 4.
The aforementioned method according to the present invention, wherein the 2-pyridone derivative having the structure of formula 1 as a starting material is prepared based on a synthetic method disclosed in the literature (Odani, r.; Hirano, k.; Satoh, t.; Miura, m.angelw.chem.int.ed.2014, 53,10784.).
Due to the application of the technical scheme, the invention has the following advantages:
the invention adopts ammonium salt and N, N-dialkyl formamide as cyanogen source for the first time, and the 6-cyano-pyridine-2-ketone derivative is synthesized by heating reaction. The reaction has the advantages of simple and easily obtained reaction raw materials and catalysts, low price, utilization of oxygen under normal pressure, mild reaction conditions, safety, high efficiency, wide reaction substrate universality, high yield of target products, simple reaction operation and post-treatment process and the like. The process of the present invention further simplifies the synthesis of 6-cyano-pyridin-2-one derivatives and the product types are further extended.
Detailed Description
The invention will now be further described with reference to the following examples:
example 1: preparation of 1- (2-pyridinyl) -6-cyanopyridin-2-one
Sequentially adding the following components into a dried schlenk tube: 1- [ 2-pyridyl ] -2-pyridone (0.2mmol, 34.4mg), anhydrous copper acetate (0.2mmol,36.3mg), ammonium iodide (0.3mmol,43.5mg), N-dimethylformamide (2 mL), an oxygen atmosphere, reacted at 130 ℃ for 20 hours, returned to room temperature, added with saturated sodium thiosulfate solution (2 mL), extracted with ethyl acetate (4 mL. times.5) several times, the organic phases were combined, and the solvent was removed on a rotary evaporator. Finally, separation by silica gel column chromatography (eluent: dichloromethane: methanol ═ 100:1) gave 1- (2-pyridyl) -6-cyanopyridin-2-one (32.7mg, isolation yield: 83%) as a pale yellow liquid.
Nuclear magnetic data: 1 H NMR(CDCl 3 500MHz):δ8.71-8.70(m,1H),7.98-7.95(m, 1H),7.56(d,J＝8.0Hz,1H),7.51-7.48(m,1H),7.46-7.42(m,1H),6.93-6.91(m, 1H),6.87-6.86(m,1H). 13 C NMR(125MHz,CDCl 3 )δ160.7,149.8,149.7,138.7, 138.4,128.0,125.1,123.1,120.7,116.1,112.2。
example 2: preparation of 1- (2-pyridinyl)]) -5-methyl-6-cyanopyridin-2-one
Sequentially adding the following components into a dried Schlenk tube: 1- [ 2-pyridyl ] -3-methyl-2-pyridone (0.2mmol,37.2mg), anhydrous copper acetate (0.2mmol,36.3mg), ammonium iodide (0.3mmol,43.5mg), N-dimethylformamide (2 mL), oxygen atmosphere, reacted at 130 ℃ for 20 hours, returned to room temperature, added with saturated sodium thiosulfate solution (2 mL), extracted with ethyl acetate (4 mL. times.5) several times, the organic phases were combined, and the solvent was removed on a rotary evaporator. Finally, separation by silica gel column chromatography (eluent: dichloromethane: methanol: 100:1) gave 1- (2-pyridyl) -5-methyl-6-cyanopyridin-2-one (33.3mg, isolated yield: 79%) as a pale yellow liquid.
Nuclear magnetic data: 1 H NMR(CDCl 3 500MHz):δ8.68(m,1H),7.94(m,1H),7.53(d, J＝8.1Hz,1H).7.48-7.46(m,1H),7.31-7.29(m,1H),6.80(d,J＝6.9Hz,1H), 2.24(s,3H). 13 C NMR(125MHz,CDCl 3 )161.4,150.2,149.7,138.7,138.5,135.3, 125.0,123.2,118.0,116.1,112.6.。
EXAMPLE 3 preparation of 1- (2-pyridinyl) -5-trifluoromethyl-6-cyanopyridin-2-one
Sequentially adding the following components into a dried Schlenk tube: 1- [ 2-pyridyl ] -3-trifluoromethyl-2-pyridone (0.2mmol,42mg), anhydrous copper acetate (0.2mmol,36.3mg), ammonium iodide (0.3mmol,43.5mg), N-dimethylformamide (2 mL), oxygen atmosphere, reaction at 130 ℃ for 20 hours, returning to room temperature, adding saturated sodium thiosulfate solution (2 mL), extracting with ethyl acetate (4 mL. times.5) for a plurality of times, combining the organic phases, and removing the solvent on a rotary evaporator. Finally, separation by silica gel column chromatography (eluent: dichloromethane: methanol 100:1) gave 1- (2-pyridyl) -5-trifluoromethyl-6-cyanopyridin-2-one (30.2 mg, isolated yield: 63%) as a pale yellow liquid.
Nuclear magnetic data: 1 H NMR(CDCl 3 500MHz):δ8.72-8.74(m,1H),8.00-7.96(m, 1H),7.86(d,J＝7.2Hz,1H),7.61-7.59(m,1H),7.55-7.52(m,1H),6.91(d,J＝ 7.2Hz,1H). 13 C NMR(125MHz,CDCl 3 )156.6,149.9,148.8,138.9,138.1(q,J＝2.5Hz),125.6,124.2,123.1,122.5,120.3,113.6,111.3。
EXAMPLE 4 preparation of 1- (2-pyridinyl) -5-chloro-6-cyanopyridin-2-one
Sequentially adding the following components into a dried Schlenk tube: 1- [ 2-pyridyl ] -3-chloro-2-pyridone (0.2mmol, 41.2mg), anhydrous copper acetate (0.2mmol,36.3mg), ammonium iodide (0.3mmol,43.5mg), N-dimethylformamide (2 mL), oxygen atmosphere, reacted at 130 ℃ for 20 hours, returned to room temperature, added with saturated sodium thiosulfate solution (2 mL), extracted with ethyl acetate (4 mL. times.5) several times, the organic phases were combined, and the solvent was removed on a rotary evaporator. Finally, separation by silica gel column chromatography (eluent: dichloromethane: methanol ═ 100:1) gave 1- (2-pyridyl) -5-chloro-6-cyanopyridin-2-one (31.9mg, isolated yield: 69%) as a pale yellow liquid.
Nuclear magnetic data: 1 H NMR(CDCl 3 500MHz):δ8.71-8.69(m,1H),7.99-7.96(m, 1H),7.65(d,J＝7.4Hz,1H),7.58-7.56(m,1H),7.53-7.51(m,1H),6.84(d,J＝ 7.5Hz,1H). 13 C NMR(125MHz,CDCl 3 )157.4,149.8,149.6,138.9,136.3,134.2, 125.5,123.0,119.1,115.2,111.9。
comparative example 1 preparation of 1- (2-pyridinyl) -6-cyanopyridin-2-one
Palladium acetate (5 mol%), anhydrous copper acetate (2 eq) in place of anhydrous copper acetate (0.2mmol,36.3mg) in example 1, isolated yield of example 1, 1- (2-pyridyl) -6-cyanopyridin-2-one: 51 percent.
Comparative example 2
Palladium acetate (5 mol%), NaOAc (2 eq.) was used in place of the anhydrous copper acetate (0.2mmol,36.3mg) in example 1, but otherwise the reaction did not occur as in example 1.
Comparative example 3
CuSO 4 ·5H 2 O (2 equiv.) was used in place of anhydrous copper acetate (0.2mmol,36.3mg) in example 1, and the reaction was not allowed to proceed as in example 1.
Comparative example 4
CuBr (2 equiv.) was used in place of anhydrous copper acetate (0.2mmol,36.3mg) in example 1, and the isolation yield of 1, 1- (2-pyridyl) -6-cyanopyridin-2-one in example 1 was otherwise the same: 33 percent.
Comparative example 5
Cu(OTf) 2 (2 equiv.) in place of anhydrous copper acetate (0.2mmol,36.3mg) in example 1, the isolation yield of 1, 1- (2-pyridyl) -6-cyanopyridin-2-one in example 1 was otherwise the same: 36 percent.
Comparative example 6
The reaction temperature was 110 ℃ and the other conditions were the same as those in example 1, isolation yield of 1- (2-pyridyl) -6-cyanopyridin-2-one: 57 percent.
Comparative example 7
The reaction temperature was 80 ℃ and the reaction did not occur under the same conditions as in example 1.
Claims (8)
1. A process for the preparation of 6-cyano-pyridin-2-one derivatives using ammonium salts and N, N-dialkylformamide as a safe cyanide source, characterized by the following steps:
(1) adding copper salt, 2-pyridone derivative shown in formula 1, ammonium salt shown in formula 2 and N, N-dialkyl formamide shown in formula 3 into a reactor, and then heating and stirring the reactor at the temperature of 100 ℃ and 150 ℃ in an oxygen atmosphere for reacting for 8-36 h;
(2) stopping the reaction, cooling to room temperature, and carrying out post-treatment to obtain the 2-cyano-6-hydroxypyridine derivative shown in the formula 4;
the reaction formula is as follows:
in the above reaction formula, R represents 1,2 or 3 substituents on the 2-pyridone ring to which it is attached, each R substituent being independently selected from hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy, -CN, -NO 2 、-OH、C 1-6 Acyl radical, C 1-6 An acyloxy group;
r 'represents 1,2, 3 or 4 substituents on the attached pyridine ring, each R' substituent being independently from each other selected from hydrogen, halogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy, -CN, -NO 2 、-OH、C 1-6 Acyl radical, C 1-6 An acyloxy group; or two adjacent R 'substituents are linked to each other and together with the carbon atom linking the two R' groups to form a five to seven membered ring, with or without heteroatoms;
x represents an anion of an ammonium salt selected from F - 、Cl - 、Br - 、I - ；
R 1 ,R 2 Independently of one another, from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl;
wherein the copper salt is selected from anhydrous copper acetate.
2. The process according to claim 1, wherein R represents 1,2 or 3 substituents on the 2-pyridone ring attached, each R substituent being independently from each other selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, acetyl, -CN, -NO 2 ；
R 'represents 1,2, 3 or 4 substituents on the attached pyridine ring, each R' substituent being independently selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, acetyl, -CN, -NO 2 (ii) a Or two adjacent R 'substituents are linked to each other and together with the carbon atom linking the two R' groups form a five to seven membered ring free of heteroatoms;
x represents an anion of an ammonium salt selected from F - 、Cl - 、Br - 、I - ；
R 1 ,R 2 Independently of one another, from methyl, ethyl, propyl, isopropyl, butyl.
3. The process according to claim 2, characterized in that R represents 1,2 or 3 substituents on the 2-pyridone ring attached, each R substituent being independently from each other selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy;
r 'represents 1,2, 3 or 4 substituents on the attached pyridine ring, each R' substituent being independently from each other selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy; or two adjacent R 'substituents are linked to each other and together with the carbon atom linking the two R' groups to form a benzene ring structure;
x represents an anion of an ammonium salt selected from I - ,
R 1 ,R 2 Independently of one another, from methyl or ethyl.
4. The method according to any one of claims 1 to 3, wherein the pressure of the oxygen atmosphere in step (1) is 1 atm.
5. The method according to any one of claims 1 to 3, wherein in step (1), the reaction temperature is 130 ℃ and the reaction time is 20 hours.
6. The method according to any one of claims 1 to 3, wherein in the step (1), the 2-pyridone derivative represented by the formula 1, the copper salt and the ammonium salt represented by the formula 2 are fed in a molar ratio of: 1 (0.5-2) and 1-3.
7. The method according to claim 6, wherein the 2-pyridone derivative represented by formula 1, the copper salt and the ammonium salt represented by formula 2 are fed in a molar ratio of: 1:1:1.5.
8. A method according to any one of claims 1 to 3, wherein in step (2), the post-processing operation is as follows: quenching the reaction liquid by using a saturated sodium thiosulfate solution, extracting by using ethyl acetate, combining organic phases, decompressing and concentrating to remove a solvent, and then separating and purifying the residue by using column chromatography, wherein the elution solvent is a mixed solvent with a dichloromethane/methanol volume ratio of 200: 1-20: 1, so as to obtain the 6-cyano-pyridine-2-ketone derivative shown in the formula 4.
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